Aspirin in the prevention of cancer

Peter Rothwell and colleagues1 provide new evidence that long-term daily aspirin lowers mortality from several common cancers. However, the mechanisms underlying this beneficial effect are not clearly understood. A plausible anti-tumour mechanism of long-term aspirin use that was not considered is aspirin-mediated chronic iron loss, as previously suggested.2

Loss of stored iron is known to be possible even in aspirin users with clinically undetectable occult gastric bleeding. Indeed, long-term aspirin use has been shown to be associated with roughly 20% lower serum ferritin concentrations—a good indicator of body iron stores—than in non-users;3 treatment with other non-steroidal anti-inflammatory drugs had no significant effect on serum ferritin concentrations.

A protective effect of iron loss on cancer mortality was confirmed in a randomised trial in which patients were randomly assigned to reduction in iron stores by calibrated phlebotomies or to observation. Over 4·5 years, the risk of new cancers was significantly lower in the iron reduction group than in controls.4 Furthermore, in patients with new cancers, those with iron reduction had highly significantly lower cancer-specific and all-cause mortality than controls. These findings are plausible in view of the growing number of published studies on the role of iron in carcinogenesis.2

In this setting, we have also proposed that lower stored iron concentrations mediated by inhibition of iron absorption by polyphenols present in the diet might exert an anti-cancer mechanism.5

Future studies of aspirin action should therefore include assessment of the effects of the intervention on iron status. If iron loss is found to be a mechanism, this consequence of aspirin use can be clinically replicated by other methods without incurring the risk of major aspirin-induced haemorrhage.2

Luca Mascitelli and Mark Goldstein raise the issue of the possible effect of aspirin treatment on iron loss as a mechanism for the reduction in cancer deaths. We deliberately did not review the many suggested mechanisms by which aspirin might reduce the risk of death due to cancer, but it is possible that reduced iron stores might contribute. There are currently insufficient data on the associations between iron stores and cancer risk to determine whether their pattern closely mirrors that of the effects of aspirin on deaths due to the specific cancers that we noted.